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siRNA Nanoparticles Validate Cancer Targets

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A tumor-targeting and tumor-penetrating nanoparticle that can deliver small interfering RNAs (siRNAs) deep into a cancer could help speed the screening and validation of putative genetic targets and also form the basis of a therapeutic siRNA platform, scientists claim. Initial in vivo experiments using the technology have validated a gene known as ID4 as a target for high-grade cancers, and demonstrated that suppressing the gene inhibits the growth of established tumors in mice and improves survival.

Developed by researchers at the Massachusetts Institute of Technology (MIT), the Dana-Farber Cancer Institute, and the Broad Institute, the targeted tumor-penetrating nanocomplex (TPN) particles comprise a gene-specific siRNA complexed with a tandem tumor-penetrating and membrane-translocating peptide.

Essentially, these nanoparticles can be designed to switch off a gene identified as a potential tumor target in cancer-bearing mice, to evaluate whether there is any therapeutic effect. This approach is much faster than generating engineered mice that either lack or overexpress the target, a process that can take years, explain MIT’s Sangeeta Bhatia, Ph.D., and Harvard Medical School’s William Hahn, Ph.D., who have spearheaded the work. Importantly, using siRNAs as gene inhibitors rather than directly inhibiting a protein, it should be possible to address otherwise undruggable targets that cant be modulated using traditional drug molecules.

Hahn heads up Project Achilles, an initiative focused on identifying new cancer targets emerging from the National Cancer Institute’s cancer genome sequencing project. The work has to date identified a number of putative targets for high-grade serous ovarian cancer (HGSC). The researchers used the nanoparticle technology to test the validity of one particular target, ID4, a helix-loop-helix (HLH) transcriptional regulator, which genome analyses studies suggest is amplified in about 32% of HGSCs, and overexpressed in most primary ovarian cancers as well as ovarian cancer cell lines and cell lines derived from a range of other cancer types.

Drs. Hahn and Bahtia teamed up to develop a TPN carrying an siRNA targeting ID4. Administering the construct to experimental mice carrying ovarian cancer tumors led to significant tumor regression and increased survival. The researchers claim their results not only validate ID4 as an oncogene in a large proportion of high-grade ovarian cancers, but also provide “a framework for the identification, validation, and understanding of potential therapeutic cancer targets.”

Their work is published in Science Translational Medicine, in a paper titled “Targeted Tumor-Penetrating siRNA Nanocomplexes for Credentialing the Ovarian Cancer Oncogene ID4.”

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